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Journal of Virology, August 2001, p. 7050-7058, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.7050-7058.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Functional Interaction between Fluorodeoxyuridine-Induced Cellular Alterations and Replication of a Ribonucleotide Reductase-Negative Herpes Simplex Virus

Henrik Petrowsky,1 Gretchen D. Roberts,1 David A. Kooby,1 Bryan M. Burt,1 Joseph J. Bennett,1 Keith A. Delman,1 Stephen F. Stanziale,1 Thomas M. Delohery,2 William P. Tong,3 Howard J. Federoff,4 and Yuman Fong1,*

Rockefeller Research Laboratories, Department of Surgery,1 Flow Cytometry Core Facility,2 and Program of Molecular Pharmacology and Therapeutics,3 Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and The Center for Aging and Developmental Biology, Aab Institute of Biomedical Science, University of Rochester Medical Center, Rochester, New York 146424

Received 17 January 2001/Accepted 16 April 2001

G207 is an oncolytic herpes simplex virus (HSV) which is attenuated by inactivation of viral ribonucleotide reductase (RR) and deletion of both gamma 134.5 genes. The cellular counterparts that can functionally substitute for viral RR and the carboxyl-terminal domain of ICP34.5 are cellular RR and the corresponding homologous domain of the growth arrest and DNA damage protein 34 (GADD34), respectively. Because the thymidylate synthetase (TS) inhibitor fluorodeoxyuridine (FUdR) can alter expression of cellular RR and GADD34, we examined the effect of FUdR on G207 bioactivity with the hypothesis that FUdR-induced cellular changes will alter viral proliferation and cytotoxicity. Replication of wild-type HSV-1 was impaired in the presence of 10 nM FUdR, whereas G207 demonstrated increased replication under the same conditions. Combined use of FUdR and G207 resulted in synergistic cytotoxicity. FUdR exposure caused elevation of RR activity at 10 and 100 nM, whereas GADD34 was induced only at 100 nM. The effect of enhanced viral replication by FUdR was suppressed by hydroxyurea, a known inhibitor of RR. These results demonstrate that the growth advantage of G207 in FUdR-treated cells is primarily based on an RR-dependent mechanism. Although our findings show that TS inhibition impairs viral replication, the FUdR-induced RR elevation may overcome this disadvantage, resulting in enhanced replication of G207. These data provide the cellular basis for the combined use of RR-negative HSV mutants and TS inhibitors in the treatment of cancer.

* Corresponding author. Mailing address: Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-2016. Fax: (212) 639-4031. E-mail: fongy{at}mskcc.org.

Journal of Virology, August 2001, p. 7050-7058, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.7050-7058.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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